Process for preparing benzoxaboroles

ABSTRACT

The present invention is a process comprising contacting a compound of formula 6: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof;
 
with a deprotecting reagent to form a compound of formula A:
 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof;
 
where R is H or OR 1 ; R 1  and each R 1′  are protecting groups; R 1″  is H or OH, and n is 0, 1, 2, 3, 4, or 5.

This application is a continuation application of U.S. application Ser.No. 13/639,594, filed Oct. 5, 2012, presently allowed, which is a UnitedStates National Phase Application of International Patent ApplicationSerial No. PCT/US2011/31384 filed Apr. 6, 2011, which claims priority toU.S. Provisional Application No. 61/321,642 filed Apr. 7, 2010; thecontents of each of the foregoing applications are hereby incorporatedby reference.

BACKGROUND OF THE INVENTION

The present invention relates to benzoxaboroles and methods for theirpreparation. The hydrochloride salt of(3S)-3-(aminomethyl)-7-[(3-hydroxypropyl)oxy]-2,1-benzoxaborol-1(3H)-ol,disclosed in U.S. patent application Ser. No. 12/142,692, now U.S. Pat.No. 7,816,344, is characterized by the following formula:

along with other pharmaceutically acceptable salts. These salts, as wellas their corresponding conjugate free base, have shown promise as anantibacterial agent, especially against Gram negative pathogens. Itwould therefore be advantageous to discover alternative ways ofpreparing this agent and its salts.

SUMMARY OF THE INVENTION

In one aspect, the present invention is a process comprisingdeprotecting a compound of formula 6:

or a pharmaceutically acceptable salt thereof;under deprotecting conditions to form a compound of formula A:

or a pharmaceutically acceptable salt thereof;where R is H or OR¹; R¹ and each R^(1′) are each protecting groups;R^(1″) is H or OH; and n is 0, 1, 2, 3, 4 or 5.

In a second aspect, the present invention is a process comprising thesteps of

a) contacting a compound of formula 2:

with nitromethane in the presence of a chiral reagent to make a compoundof formula 3:

where R is H or OR¹; R¹ is a protecting group; and n is 0, 1, 2, 3, 4 or5;b) reducing the compound of formula 3 to form a compound of formula 4:

c) contacting the compound of formula 4 or a salt thereof with R^(1′)Xwith a base to form a compound offormula 5:

or a salt thereof, wherein R^(1′) is a protecting group and X is aleaving group;d) contacting the compound of formula 5 or a salt thereof with aborylating reagent characterized by the following formula:

in the presence of n-BuLi to form a compound of formula 6:

or a pharmaceutically acceptable salt thereof,where each R² is independently C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl,C₅-alkyl, C₆-alkyl, or together with the oxygen atoms to which they areattached form a 5- or 6-membered ring; and R³ is C₁-alkyl, C₂-alkyl,C₃-alkyl, C₄-alkyl, C₅-alkyl, C₆-alkyl; ande) deprotecting the compound of formula 6 or a pharmaceuticallyacceptable salt thereof to form a compound of formula A or apharmaceutically acceptable salt thereof:

where R^(1″) is H or OH.

In another aspect the present invention is a process comprising thesteps of:

a) brominating a compound of formula 8:

to form a compound of formula 9:

where R is H or OR¹; R¹ is a protecting group; and n is 0, 1, 2, 3, 4 or5;b) contacting the compound of formula 9 with HN(R^(1′))₂ to form acompound of formula 10:

or a salt thereof,where each R^(1′) is a protecting group;c) enantioselectively reducing the compound of formula 10 to form acompound of formula 5:

d) contacting the compound of formula 5 or a salt thereof with aborylating reagent characterized by the following formula:

in the presence of n-BuLi, to form a compound of formula 6:

or a pharmaceutically acceptable salt thereof,where each R² is independently C₁-C₆-alkyl, or together with the oxygenatoms to which they are attached form [as above] a 5- or 6-memberedring; and R³ is C₁-C₆-alkyl; ande) deprotecting the compound of formula 6 or a pharmaceuticallyacceptable salt thereof to form a compound of formula A or apharmaceutically acceptable salt thereof:

where R^(1″) is H or OH.

In another aspect, the present invention is a compound characterized bythe following formula 6a:

or a pharmaceutically acceptable salt thereof,where R^(1″) is H or OH; and R^(1′) is a protecting group.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention is a process comprisingdeprotecting a compound of formula 6:

or a pharmaceutically acceptable salt thereof;under deprotecting conditions to form a compound of formula A:

or a pharmaceutically acceptable salt thereof;where R is H or OR¹; R¹ and each R^(1′) are protecting groups; leis H orOH; and n is 0, 1, 2, 3, 4, or 5.

Examples of suitable R¹ protecting groups include—CH(R^(a))-phenyl-(R^(b))_(x), trialkylsilyl, tetrahydropyranyl,—CH₂OCH₃, or —CH₂OCH₂CH₂OCH₃ groups, where R^(a) is H, C₁-alkyl,C₂-alkyl, C₃-alkyl, C₄-alkyl or phenyl; each R^(b) is independentlyC₁-alkyloxy, C₂-alkyloxy, C₃-alkyloxy, C₄-alkyloxy; or C₁-alkyl,C₂-alkyl, C₃-alkyl, C₄-alkyl; and x is 0, 1, or 2. In another aspect, R¹is benzyl.

C₁-C₁-alkyl refers to C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and t-butyl.Similarly, C₁-C₄-alkoxy refers to C₁-alkyloxy, C₂-alkyloxy, C₃-alkyloxy,C₄-alkyloxy e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,sec-butoxy, and t-butoxy. C₁-C₆-alkyl refers to C₁-alkyl, C₃-alkyl,C₄-alkyl, C₅-alkyl, C₆-alkyl.

Examples of suitable R^(1′) protecting groups include—CH(R^(b))-phenyl-(R^(c))_(y); examples of such groups include benzyl,1-phenylethyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl,2,4-dimethoxybenzyl, and diphenylmethyl groups; in another aspect, eachR^(1′) is benzyl.

Suitable deprotection methods include metal catalyzed hydrogenation,catalytic transfer hydrogenation, or acid cleavage. Where R′ is benzyl,preferred deprotection reagents include H₂ over Pd/C, H₂ over Pt/C, H₂over palladium hydroxide, or ammonium formate and Pd/C.

In another aspect, n is 0, 1, 2 or 3; preferably, n is 2.

As used herein, “a pharmaceutically acceptable salt” refers to an acidaddition salt. Examples of suitable acid addition salts are inorganicacid salts and organic salts; Examples of suitable inorganic saltsinclude hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric,and sulfuric acid salts; examples of suitable organic acid salts includetartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric,benzoic, formic, propionic, glycolic, gluconic, maleic, succinic,methanesulfonic, ethanesulfonic, stearic, benzenesulfonic,bromobenzenesulfonic, and p-toluenesulfonic acid salts. Thepharmaceutically acceptable salt of A is preferably an HCl salt.

In another aspect, the compound of formula 6 is reduced in the presenceof HCl to form the hydrochloride salt of the compound of formula A.

In another aspect of the present invention, the compound of formula 6 isprepared by contacting a compound of formula 5:

or a salt thereof with a borylating reagent in the presence of analkyllithium such as n-BuLi, n-hexyllithium, or sec-BuLi.

The borylating reagent is characterized by the following formula:

Each R² is independently C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl,C₅-alkyl, C₆-alkyl and each R³ is C₁-alkyl, C₂-alkyl, C₃-alkyl,C₄-alkyl, C₅-alkyl, C₆-alkyl. Preferably, each R² is the same alkylgroup; alternatively, the R² groups, together with the oxygen atoms towhich they are attached form a 5- or 6-membered ring, which may beoptionally fused to an aryl ring. Examples of suitable borylatingreagents include isopropylpinacolborate,2-(methoxy)-1,3,2-benzodioxaborole, and tri-C₁-borates, tri-C₂-boratesand tri-C₃-borates such as triisopropyl borate and trimethyl borate. Inanother aspect, the borylating reagent is isopropylpinacolborate ortrimethyl borate.

The compound of formula 5 or a salt thereof can be prepared bycontacting under basic conditions R^(1′)X with a compound of formula 4:

or a salt thereof,wherein X is a suitable leaving group such as a Br, Cl, I, tosyl, ortriflyl group. Suitable bases include carbonates such as sodiumpotassium, and cesium carbonates, or hydroxides such astetrabutylammonium hydroxide.

The compound of formula 4 or a salt thereof can be prepared bycontacting a compound of formula 2:

with nitromethane in the presence of a chiral reagent, to form acompound of formula 3:

then reducing the nitro group to an amine group.

Examples of suitable chiral reagents include1,7,7-trimethyl-N-(pyridin-2-ylmethyl)bicyclo[2.2.1]heptan-2-aminedi-hydrochloride;(4S)-4-ethyl-2-{1-ethyl-1-[(4S)-4-(1-methylethyl)-4,5-dihydro-1,3-oxazol-2-yl]propyl}-4,5-dihydro-1,3-oxazole;(S)-4-(tert-butyl)-2-(2-((S)-4-methyl-4,5-dihydrooxazol-2-yl)propan-2-yl)-4,5-dihydrooxazole;orN1,N2-bis[(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1,2-ethanediaminein the presence of a suitable catalyst such as Co(OAc)₂, Cu(OAc)₂,CuCl₂, Zn(OTf)₂, or Zn(Et)₂.

Examples of suitable nitro-reducing agents would include Pd/C, Pt/C or amixture thereof, in the presence of hydrogen.

The compound of formula 2 is conveniently prepared by reaction ofR¹(CH₂)₃—X with 3-hydroxybenzaldehyde in the presence of a suitablebase, examples of which include hydroxide and carbonate bases.

Alternatively, the compound of formula 5 or a salt thereof can beprepared by enantioselective reduction of a compound of formula 10:

or a salt thereof.

Examples of an enantioselective reduction reagents include H₂ andruthenium-, rhodium- or iridium-based catalyst such as(S)-2-[(S_(P))-2-(diphenylphosphino)ferrocenyl]-4-isopropyl-2-oxazolinetriphenylphosphine ruthenium(II) dichloride complex (also known as Naudcatalyst); (R)-BINAP-Ru-(R,R)-(+)-DPEN Cl (also known as Noyoricatalyst), or oxazaborolidine-catalyzed borane reduction.

The compound of formula 10 or a salt thereof can be prepared bycontacting HN(R^(1′))₂ with a compound of formula 9:

The compound of formula 9 can be prepared by bromination of a compoundof formula 8:

Suitable brominating reagents include Br₂ in dichloromethane, NBS, andtetra-n-butylammonium tribromide.

Compound 8 is prepared by contacting 3-hydroxyacetophenone withX(CH₂)₃—R¹ and a suitable base, examples of which include hydroxide andcarbonate bases.

Schemes

The following schemes generally illustrate the processes of the presentinvention. R¹ R^(1′), and X are not limited to the groups specificallydisclosed, nor are the processes limited to the disclosed catalysts,bases, reducing agents, and enantioselective reagents.

In accordance with Scheme 1, 3-hydroxybenzaldehyde (compound 1) iscontacted with XCH₂(CH₂)_(n)CH₂R in the presence of a suitable baseunder conditions sufficient to form compound 2.

Compound 2 is converted to the corresponding(1S)-2-nitro-1-phenylethanol (compound 3) using nitromethane and asuitable chiral reagent such as1,7,7-trimethyl-N-(pyridin-2-ylmethyl)bicyclo[2.2.1]heptan-2-aminedi-hydrochloride;(4S)-4-ethyl-2-{1-ethyl-1-[(4S)-4-(1-methylethyl)-4,5-dihydro-1,3-oxazol-2-yl]propyl}-4,5-dihydro-1,3-oxazole;(S)-4-(tert-butyl)-2-(2-((S)-4-methyl-4,5-dihydrooxazol-2-yl)propan-2-yl)-4,5-dihydrooxazole;orN1,N2-bis[(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1,2-ethanediaminein the presence of a suitable catalyst such as Cu(OAc)₂. Compound 3 isthen converted to the corresponding primary amine (compound 4) thenprotected with R^(1′)X to form compound 5; this intermediate may beisolated as the free base or as a salt, preferably the hydrochloridesalt.

Compound 5 or a salt thereof is borylated with a suitable borylatingreagent in the presence of a strong base such as n-BuLi, n-hexyllithium,or sec-BuLi to form Compound 6. This intermediate is deprotected to formthe aminomethyl benzoxaborole, preferably(3S)-3-(aminomethyl)-7-[(3-hydroxypropyl)oxy]-2,1-benzoxaborol-1(3H)-ol.This product is advantageously isolated as a hydrochloride salt, and canbe further purified by way of recrystallization.

In accordance with Scheme 2, 3-hydroxyacetophenone (compound 7) iscontacted with XCH₂(CH₂)_(n)CH₂—R in the presence of a suitable baseunder conditions sufficient to form compound 8. Bromination with asuitable brominating reagent results in the formation of the bromoketone(compound 9), which in turn is contacted with HN(R^(1′))₂ underconditions sufficient to form the protected amine (compound 10).

Compound 10 or a salt thereof is enantioselectively reduced to thecorresponding (1S)-2-amino-1-phenylethanol (Compound 5) underenantioselective reductions conditions.

Compound 5 or a salt thereof is then borylated and deprotected asdescribed in Scheme 1 to form the aminomethyl benzoxaborole, preferably(3S)-3-(aminomethyl)-7-[(3-hydroxypropyl)oxy]-2,1-benzoxaborol-1(3H)-ol,preferably as the hydrochloride salt.

The following examples are illustrative of the process of the presentinvention and are not intended to limit the scope of the invention.

Example 1 Preparation of(3S)-3-(Aminomethyl)-7-[(3-hydroxypropyl)oxy]-2,1-benzoxaborol-1(3H)-olHydrochloride 1A. Preparation of3-({3-[(Phenylmethyl)oxy]propyl}oxy)benzaldehyde

To a 3-L reaction vessel was charged and stirred cesium carbonate (209.6g), 3-hydroxybenzaldehyde (67.6 g), dimethylformamide (DMF, 250 mL) and3-bromopropyl phenylmethyl ether (113.4 g) at ambient temperature for˜18 h. Water (567 mL) was added followed by tert-butyl methyl ether (907mL). The bottom aqueous layer was separated and the organic layer washedwith 1N sodium hydroxide (2×567 mL) and water (1×567 mL). The organicsolution was concentrated to a minimum after which ethanol (200 proof,907 mL) was added and the solution concentrated to a minimum andfiltered though a 1-μm filter.

1B. Preparation of(1S)-2-Nitro-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol

Copper (II) acetate and camphoraminomethylpyridine bis-HCl salt (504 mg)were charged to a reactor, followed by ethanol (60 mL) anddiisopropylethylamine (1.16 mL). The contents were stirred for 1 h atroom temperature, at which time a solution of3-({3-[(phenylmethyl)oxy]propyl}oxy)benzaldehyde in ethanol (15 g in 15mL) was charged. The reaction mixture was cooled to −30° C. to −40° C.,whereupon nitromethane (33.9 g) was added slowly to the reaction,maintaining a temperature below −30° C., followed bydiisopropylethylamine (359 mg). The reaction temperature was maintainedat −30° C. for 24-48 h. When the reaction was complete, trifluoroaceticacid (952 mg) was charged to the reaction, and the contents weretransferred to a separate reactor containing a room temperature solutionof 1 N HCl (75 mL) and t-butyl methyl ether (TBME, 150 mL). After theaddition was complete, the layers were allowed to separate and theaqueous phase removed. The organic phase was then washed with water (75mL) and the aqueous phase removed. The solution of product in TBME wasthen filtered through a pad of silica gel (15 g) which was rinsed withTBME. The product was stored cold as a solution in TBME, to be swappedto ethanol prior to the subsequent hydrogenation step.

1C1. Preparation of(1S)-2-Amino-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol

The (1S)-2-nitro-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanolin ethanol solution (8 g in 160 mL) was hydrogenated using a Pd(4%)/Pt(1%)/C catalyst (1.6 g). Upon consumption of the startingmaterial and the hydroxylamine intermediate, the reaction product inethanol was filtered.

1C2. Preparation of(1S)-2-[Bis(phenylmethyl)amino]-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanolhydrochloride

Powdered potassium carbonate (12.8 g) was charged to a 250-mL reactor,followed by the ethanolic solution of(1S)-2-amino-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol (12.7g in 100 mL). Additional ethanol was charged into the slurry (40 mL).Benzyl bromide (15.9 g) was charged to the reactor, and the slurry wasstirred at 20-25° C. for 18 h-24 h, after which time, the solids werefiltered and washed with ethanol (50 mL). The filtrate was diluted withwater (50 mL) then heated to 50° C. Concentrated HCl (3.52 mL) wascharged to the reactor resulting the precipitation of the HCl salt ofthe product. At the onset of precipitation, the slurry was held at 50°C. for 30 min, then cooled to 0° C. and held at 0° C. for an additional30 min. The product was filtered and washed with a 0° C. solution of 20%aqueous ethanol (˜60 mL).

1D. Preparation of(3S)-3-{[Bis(phenylmethyl)amino]methyl}-7-({3-[(phenylmethyl)oxy]propyl}oxy)-2,1-benzoxaborol-1(3H)-ol

(1S)-2-[Bis(phenylmethyl)amino]-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanolhydrochloride (20 g) and toluene (160 mL) were charged into the 250-mLreactor. The contents were mixed thoroughly for about 5 min after whichthe mixture was degassed by placing the reactor under vacuum andbackfilling with nitrogen; and repeating two times. The suspension washeated to 50-55° C., at which time nBuLi (16.3 mL, 2.6 M) was added overabout 1 h with vigorous mixing. The mixture was then stirred for about 1h at 50-55° C., at which time the starting material was observed to beconsumed. The mixture was then cooled to −20 to −40° C. whereupon 1.0equiv of nBuLi (14.8 mL) was added at such a rate to maintain thetemperature to below −20° C. Upon completion of addition, thetemperature was adjusted to −30 to −40° C. and nBuLi (43 mL) was addedas quickly as possible (<10 minutes) while still keeping the temperaturebelow −20° C. during addition. The temperature was adjusted to −20 to−25° C. and stirred for 1 hr. The mixture was cooled to −75 to −80° C.and an aliquot was quenched directly into CD₃OD. Once complete deuteriumincorporation was observed, evidenced by LCMS, THF (18 mL) was addeddirectly followed by rapid addition of the borate (36 mL). The mixturewas warmed to 15-25° C. over 30 min to 1 h, 5% aq. NaHCO₃ (200 mL) wasthen added and the mixture was stirred vigorously for ˜15 min. Theresulting suspension was filtered and the cake rinsed with at least 30mL of TBME. The filtrate was allowed to separate and the organic layerwas then washed three or four times with water (100 mL), allowing thelast wash at least 1 h to settle. The organic layer was concentrated toabout 40 mL.

1E. Preparation of(3S)-3-(Aminomethyl)-7-[(3-hydroxypropyl)oxy]-2,1-benzoxaborol-1(3H)-olhydrochloride

To a solution of(3S)-3-(aminomethyl)-7-[(3-hydroxypropyl)oxy]-2,1-benzoxaborol-1(3H)-olhydrochloride in toluene (˜46 mL) was added methanol (200 mL), 1 N HClin water (42.5 mL), and 5% Pd/C catalyst (2 g, 11 wt %). The resultingmixture was treated with hydrogen gas at 100 psig and 50° C. Uponconsumption of the mono N-benzyl amine intermediate, the reactionsolution was filtered through a filtering aid, followed by a 1 μmfiltration. The filtered solution of crude product was then distilled,2-propanol added (200 mL), then distilled again to minimum stirrablevolume. This concentrated solution was allowed to crystallize at roomtemperature, then filtered and washed with 2-propanol. NMR:(d4-methanol, 400.13 MHz) δ (ppm) 7.48 (t, J=7.81 Hz, 1H), 7.01 (d,J=7.58 Hz, 1H), 6.93 (d, J=8.21 Hz, 1H), 5.37 (dd, J=2.76, 8.77 Hz, 1H),4.18 (t, J=6.11 Hz, 2H), 3.78 (t, J=5.47 Hz, 2H), 3.59 (dd, J=2.87,13.29 Hz, 1H), 2.92 (dd, J=8.86, 13.29 Hz, 1H), 2.00 (m, J=6.13 Hz, 2H).The accurate mass of the protonated molecule of [M+H]⁺ was measured atm/z 238.1247 using positive ion electrospray ionization. The calculatedmass of this ion is at m/z 238.1251. Chiral purity was found to be 99.9%using chiral HPLC.

Example 2 Preparation of(3S)-3-(Aminomethyl)-7-[(3-hydroxypropyl)oxy]-2,1-benzoxaborol-1(3H)-olHydrochloride 2A. Preparation of3-({3-[(Phenylmethyl)oxy]propyl}oxy)benzaldehyde

To a 3-L reaction vessel was charged and stirred potassium carbonate(152 g), 3-hydroxybenzaldehyde (67.6 g), dimethylformamide (DMF, 250 mL)and 3-chloropropyl phenylmethyl ether (96.4 g) at 90° C. for 18 h. Water(567 mL) was added followed by tert-butyl methyl ether (907 mL). Thebottom aqueous layer was separated and the organic layer washed with 1Nsodium hydroxide (2×567 mL) and water (1×567 mL). The organic solutionwas concentrated to a minimum after which ethanol (200 proof, 907 mL)was added and the solution concentrated to a minimum and filtered thougha 1-μm filter.

2B. Preparation of(1S)-2-Nitro-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol

Copper (II) acetate monohydrate (3.70 g, 0.05 eq) andbis-camphorethylenediamine(N1,N2-bis[(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1,2-ethanediamine)(7.38 g, 0.06 eq) were charged to a reactor, followed by ethanol (200mL, 2 vol). The contents were heated to 50-60° C. for 1 h or until allsolids dissolved, then cooled to room temperature and stirred, at whichtime a solution of 3-({3-[(phenylmethyl)oxy]propyl}oxy)benzaldehyde inethanol (100 g, 1 eq in 50 mL, 0.5 vol) was charged. The reactionmixture was cooled to −10° C. to −20° C., whereupon nitromethane (112.7g, 5 eq) was added slowly to the reaction, maintaining a temperaturebelow −10° C., followed by diisopropylethylamine (1.94 mL, 1.44 g, 0.03eq). The reaction temperature was maintained at −10° C. for 22-30 h.When the reaction was complete, a room temperature solution of 1 N HCl(250 mL, 2.5 vol) and t-butyl methyl ether (TBME, 500 mL, 5 vol) werecharged to the reaction vessel. Following the addition, the contentswere stirred for 5 minutes and brought to 20° C. (room temperature), andthen the layers were allowed to separate and the aqueous phase removed.The organic phase was then washed 2× with water (250 mL, 2.5 vol) andeach time the aqueous phase removed. TBME was then distilled off andreplaced with absolute ethanol.

2C1. Preparation of(1S)-2-Amino-1-[3-({3[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol

The (1S)-2-nitro-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanolin ethanol solution (8 g in 160 mL) was hydrogenated using a Pd(4%)/Pt(1%)/C catalyst (1.6 g). Upon consumption of the startingmaterial and the hydroxylamine intermediate, the reaction product inethanol was filtered.

2C2. Preparation of(1S)-2-[Bis(phenylmethyl)amino]-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanolhydrochloride

Powdered potassium carbonate (12.8 g) was charged to a 250-mL reactor,followed by the ethanolic solution of(1S)-2-amino-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol (12.7g in 100 mL). Additional ethanol was charged into the slurry (40 mL).Benzyl bromide (15.9 g) was charged to the reactor, and the slurry wasstirred at 20-25° C. for 18 h-24 h, after which time, the solids werefiltered and washed with ethanol (50 mL). The filtrate was diluted withwater (50 mL) then heated to 50° C. Concentrated HCl (3.52 mL) wascharged to the reactor resulting the precipitation of the HCl salt ofthe product. At the onset of precipitation, the slurry was held at 50°C. for 30 min, then cooled to 0° C. and held at 0° C. for an additional30 min. The product was filtered and washed with a 0° C. solution of 20%aqueous ethanol (60 mL).

2D. Preparation of(3S)-3-{[Bis(phenylmethyl)amino]methyl}-7-({3-[(phenylmethyl)oxy]propyl}oxy)-2,1-benzoxaborol-1(3H)-ol

(1S)-2-[Bis(phenylmethyl)amino]-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanolhydrochloride (20 g) and toluene (160 mL) were charged into the 250-mLreactor. The contents were mixed thoroughly for about 5 min after whichthe mixture was degassed by placing the reactor under vacuum andbackfilling with nitrogen; and repeating two times. The suspension washeated to 50-55° C., at which time nBuLi (16.3 mL, 2.6 M) was added overabout 1 h with vigorous mixing. The mixture was then stirred for about 1h at 50-55° C., at which time the starting material was observed to beconsumed. The mixture was then cooled to −20 to −40° C. whereupon 1.0equiv of nBuLi (14.8 mL) was added at such a rate to maintain thetemperature to below −20° C. Upon completion of addition, thetemperature was adjusted to −30 to −40° C. and nBuLi (43 mL) was addedas quickly as possible (<10 minutes) while still keeping the temperaturebelow −20° C. during addition. The temperature was adjusted to −20 to−25° C. and stirred for 1 hr. The mixture was cooled to −75 to −80° C.and an aliquot was quenched directly into CD₃OD. Once complete deuteriumincorporation was observed, evidenced by LCMS, THF (18 mL) was addeddirectly followed by rapid addition of the borate (36 mL). The mixturewas warmed to 15-25° C. over 30 min to 1 h, 5% aq. NaHCO₃ (200 mL) wasthen added and the mixture was stirred vigorously for ˜15 min. Theresulting suspension was filtered and the cake rinsed with at least 30mL of TBME. The filtrate was allowed to separate and the organic layerwas then washed three or four times with water (100 mL), allowing thelast wash at least 1 h to settle. The organic layer was concentrated toabout 40 mL.

2E. Preparation of(3S)-3-(Aminomethyl)-7-[(3-hydroxypropyl)oxy]-2,1-benzoxaborol-1(3H)-olhydrochloride

To a solution of(3S)-3-(aminomethyl)-7-[(3-hydroxypropyl)oxy]-2,1-benzoxaborol-1(3H)-olhydrochloride in toluene (˜46 mL) was added methanol (200 mL), 1 N HClin water (42.5 mL), and 5% Pd/C catalyst (2 g, 11 wt %). The resultingmixture was treated with hydrogen gas at 100 psig and 50° C. Uponconsumption of the mono N-benzyl amine intermediate, the reactionsolution was filtered through a filtering aid, followed by a 1 μmfiltration. The filtered solution of crude product was then distilled,2-propanol added (200 mL), then distilled again to minimum stirrablevolume. This concentrated solution was allowed to crystallize at roomtemperature, then filtered and washed with 2-propanol. ¹H NMR:(d4-methanol, 400.13 MHz) δ (ppm) 7.48 (t, J=7.81 Hz, 1H), 7.01 (d,J=7.58 Hz, 1H), 6.93 (d, J=8.21 Hz, 1H), 5.37 (dd, J=2.76, 8.77 Hz, 1H),4.18 (t, J=6.11 Hz, 2H), 3.78 (t, J=5.47 Hz, 2H), 3.59 (dd, J=2.87,13.29 Hz, 1H), 2.92 (dd, J=8.86, 13.29 Hz, 1H), 2.00 (m, J=6.13 Hz, 2H).The accurate mass of the protonated molecule of [M+H]⁺ was measured atm/z 238.1247 using positive ion electrospray ionization. The calculatedmass of this ion is at m/z 238.1251. Chiral purity was found to be 99.9%using chiral HPLC.

Example 3 Alternative Preparation of(3S)-3-(Aminomethyl)-7-[(3-hydroxypropyl)oxy]-2,1-benzoxaborol-1(3H)-olHydrochloride 3A. Preparation of1-[3-({3-[(Phenylmethyl)oxy]propyl}oxy)phenyl]ethanone

To a solution of 3-hydroxyacetophenone (5.5 g) in dimethylformamide (18mL) was added 3-bromopropyl phenylmethyl ether (9.25 g) at ambienttemperature followed by cesium carbonate (17 g). The suspension wasstirred for 24 h and water was added followed by ethyl acetate. Theorganic layer was separated and the aqueous layer extracted with ethylacetate. The organic layers were combined and washed twice with 2 Nsodium hydroxide, four times with brine, and concentrated in vacuo to anoil to give the title compound.

3B. Preparation of2-Bromo-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone

To a solution of 1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone(10.59 g) in tetrahydrofuran (50 mL) was added methanol (50 mL) and asolution of tetrabutylammonium tribromide (16 g) in tetrahydrofuran (50mL). The reaction was stirred at ambient temperature for 45 min at whichtime tetrabutylammonium tribromide (0.89 g) was added, followed byfurther addition of 0.6 g. 10% aqueous sodium thiosulfate was added tothe reaction and the mixture was concentrated in vacuo to a minimumvolume. Ethyl acetate was added and the resultant organic solution waswashed with aqueous sodium thiosulfate, saturated sodium bicarbonate andbrine and concentrated to an oil to afford the title compound.

3C. Preparation of2-[Bis(phenylmethyl)amino]-1-[3-({3[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone

To a mixture of2-bromo-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone (13.17g), dibenzylamine (6.4 g) and dichloromethane (25 mL) was added asolution of sodium carbonate (7.6 g) in water (50 mL). The reactionmixture was stirred at ambient temperature overnight. The organic layerwas separated and concentrated to a minimum and tert-butyl methyl etherwas added. The organic layer was washed with dilute acetic acid (4times) and 0.1 N sodium hydroxide once and brine once. The organicsolution was concentrated to dryness. The oil was washed with methanoland purified by chromatography to give the title compound.

3D: Preparation of(1S)-2-[bis(phenylmethyl)amino]-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol

A mixture of2-[bis(phenylmethyl)amino]-1-[3-({3[(phenylmethyl)oxy]propyl}oxy)phenyl]-ethanone,catalyst SK-N003-2z (Naud catalyst, 47 mg) and 1M sodium hydroxide(2.085 mL) in tetrahydrofuran (10 mL) was set under hydrogen at 150 psifor 4 h. The reaction mixture was then filtered through silica gel. Thecrude filtrate was purified by chromatography eluting with tert-butylmethyl ether-hexane (0-60%) to yield the desired product as a yellowoil.

3E: Preparation of(3S)-3-{[bis(phenylmethyl)amino]methyl}-7-({3-[(phenylmethyl)oxy]propyl}oxy)-2,1-benzoxaborol-1(3H)-ol

To a solution of(1S)-2-[bis(phenylmethyl)amino]-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol(240 mg, 0.50 mmol) in 5 mL of toluene at −20° C. was added 1.75 mmol ofnBuLi in hexane (2.59 M, 0.67 mL) over about 5 minutes. The mixture wasthen stirred for 2 h and then quenched with freshly distilledtrimethylborate (0.28 mL, 259 mg, 2.5 mmol). The cold bath was removedand the mixture warmed to room temperature. The reaction was thendiluted with 10 mL of TBME, then 5 mL of saturated NaHCO₃ solution wasadded. After vigorously stirring for about 30 min, the organic layer waswashed with 5 mL of 0.1 M NaH₂PO₄, then 5 mL of saturated NaHCO₃. Theorganic layer was then dried over Na₂SO₄ and concentrated.

1. A process comprising contacting a compound of formula 6:

or a pharmaceutically acceptable salt thereof; with a deprotectingreagent to form a compound of formula A:

or a pharmaceutically acceptable salt thereof; where R is H or OR¹; R¹and each R^(1′) are each independently protecting groups; R^(1″) is H orOH; and n is 0, 1, 2, 3, 4 or
 5. 2. The process of claim 1 wherein R isOR¹; R¹ is —CH(R^(a))-phenyl-(R^(b))_(x), trialkylsilyl,tetrahydropyranyl, —CH₂OCH₃, or —CH₂OCH₂CH₂OCH₃ groups, where R^(a) is Hor methyl; R^(b) is methoxy or C₁-alkyl, C₂-alkyl, or C₃-alkyl; and x is0, 1 or 2; and each R^(1′) is independently—CH(R^(c))-phenyl-(R^(d))_(y), where R^(c) is H or methyl, each R^(d) isindependently methoxy or C₁-alkyl, C₂-alkyl, or C₃-alkyl; n is 0, 1, 2or 3, and y is 0, 1 or
 2. 3. The process of claim 1 wherein R is OR¹; R¹and each R^(1′) are benzyl groups; the deprotecting reagent is areducing reagent; n is 1; and the compound of formula 6 is reduced inthe presence of HCl to form the hydrochloride salt of the compound offormula A.
 4. The process of claim 3 wherein the deprotecting reagent isPd/C or Pt/C in the presence of H₂ or a mixture thereof, H₂ overpalladium hydroxide, or catalytic transfer hydrogenating reagentconditions.
 5. The process of any of claims 1 to 4 wherein the compoundof formula 6 is prepared by contacting a compound of formula 5:

or a salt thereof with a borylating reagent characterized by thefollowing formula:

in the presence of an alkylithium reagent, where each R² isindependently C₁-C₆-alkyl, or together with the oxygen atoms to whichthey are attached form a 5- or 6-membered ring; and R³ is C₁-alkyl,C₃-alkyl, C₄-alkyl, C₅-alkyl, C₆-alkyl.
 6. The process of claim 5wherein the borylating reagent is isopropylpinacolborate, or atri-C₁-borate, tri-C₂-borate or tri-C₃-borate; n is 0 to 3; and thealkyl lithium reagent is n-BuLi, n-hexyllithium, or sec-BuLi.
 7. Theprocess of either claim 5 or 6 wherein the borylating reagent isisopropylpinacolborate or trimethyl borate; n is 2 and the alkyl lithiumreagent is n-BuLi.
 8. The process of claim 5 wherein the compound offormula 5 or a salt thereof is prepared either by enantioselectivereduction of a compound of formula 10

or a salt thereof; or by contacting under basic conditions R^(1′)X witha compound of formula 4:

or a salt thereof, where X is a leaving group.
 9. The process of claim 8wherein the compound of formula 5 or a salt thereof is prepared using H₂and Naud catalyst or H₂ and Noyori catalyst; and n is
 2. 10. The processof claim 8 wherein the compound of formula 5 or a salt thereof isprepared by contacting the compound of formula 4 or a salt thereof withbenzyl bromide in the presence of a carbonate or a hydroxide.
 11. Theprocess of claim 10 wherein the compound of formula 4 or a salt thereofis prepared by contacting formula 2:

with nitromethane in the presence of a chiral reagent, to form acompound of formula 3:

then reducing the nitro group to an amine group.
 12. The process ofclaim 11 wherein the chiral reagent is1,7,7-trimethyl-N-(pyridin-2-ylmethyl)bicyclo[2.2.1]heptan-2-aminedi-hydrochloride; (4S)-4-ethyl-2-{1-ethyl-1-[(4S)-4-(1-methylethyl)-4,5-dihydro-1,3-oxazol-2-yl]propyl}-4,5-dihydro-1,3-oxazole;(S)-4-(tert-butyl)-2-(2-((S)-4-methyl-4,5-dihydrooxazol-2-yl)propan-2-yl)-4,5-dihydrooxazole;orN1,N2-bis[(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1,2-ethanediamineand Cu(OAc)₂; and n is
 2. 13. The process of claim 8 wherein thecompound of formula 10 or a salt thereof is prepared by contactingHN(R^(1′))₂ with a base and a compound of formula 9:


14. The process of claim 13 wherein the compound of formula 9 isprepared by bromination of a compound of formula 8:


15. A process comprising the steps of: a) contacting a compound offormula 2:

with nitromethane in the presence of a chiral reagent to make a compoundof formula 3:

where R is H or OR¹; R¹ is a protecting group; and n is 0, 1, 2, 3, 4 or5; b) reducing the compound of formula 3 to form a compound of formula4:

or a salt thereof; c) contacting the compound of formula 4 or a saltthereof with R^(1′)X with a base to form a compound of formula 5:

or a salt thereof, wherein R^(1′) is a protecting group and X is aleaving group; d) contacting the compound of formula 5 or a salt thereofwith a borylating reagent characterized by the following formula:

in the presence of n-BuLi to form a compound of formula 6:

or a pharmaceutically acceptable salt thereof, where each R² isindependently C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl,C₆-alkyl, or together with the oxygen atoms to which they are attachedform a 5- or 6-membered ring; and R³ is C₁-alkyl, C₂-alkyl, C₃-alkyl,C₄-alkyl, C₅-alkyl, C₆-alkyl; and e) contacting the compound of formula6 or a pharmaceutically acceptable salt thereof with a deprotectingreagent to form a compound of formula A or a pharmaceutically acceptablesalt thereof:

where R^(1″) is H or OH.
 16. The process of claim 15 wherein: R¹ andeach R^(1′) are benzyl groups; n is 2; the chiral reagent is Cu(OAc)₂and 1,7,7-trimethyl-N-(pyridin-2-ylmethyl)bicyclo[2.2.1]heptan-2-aminedi-hydrochloride;(4S)-4-ethyl-2-{1-ethyl-1-[(4S)-4-(1-methylethyl)-4,5-dihydro-1,3-oxazol-2-yl]propyl}-4,5-dihydro-1,3-oxazole;(S)-4-(tert-butyl)-2-(2-((S)-4-methyl-4,5-dihydrooxazol-2-yl)propan-2-yl)-4,5-dihydrooxazole;orN1,N2-bis[(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1,2-ethanediamine;X is a leaving group selected from Br, Cl, I, tosyl or triflyl; theborylating reagent is isopropylpinacolborate or trimethylborate; and thedeprotecting agent is hydrogenation in the presence of a Pd/C catalyst,Pt/C catalyst or a mixture of Pd/C+Pt/C catalysts.
 17. A processcomprising the steps of: a) brominating a compound of formula 8:

to form a compound of formula 9:

where R is H or OR¹; R¹ is a protecting group; and n is 0, 1, 2, 3, 4 or5; b) contacting the compound of formula 9 with HN(R^(1′))₂ to form acompound of formula 10:

or a salt thereof, where each R^(1′) is a protecting group; c)enantioselectively reducing the compound of formula 10 or a salt thereofto form a compound of formula 5:

or a salt thereof; d) contacting the compound of formula 5 or a saltthereof with a borylating reagent characterized by the followingformula:

in the presence of n-BuLi, to form a compound of formula 6:

or a pharmaceutically acceptable salt thereof, where each R² isindependently C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl,C₆-alkyl, or together with the oxygen atoms to which they are attachedform a 5- or 6-membered ring; and R³ is C₁-alkyl, C₂-alkyl, C₃-alkyl,C₄-alkyl, C₅-alkyl, C₆-alkyl; and e) contacting the compound of formula6 or a pharmaceutically acceptable salt thereof with a deprotectingreagent to form a compound of formula A or a pharmaceutically acceptablesalt thereof:

where R^(1″) is H or OH.
 18. A compound of formula 6a:

or a pharmaceutically acceptable salt thereof, where R^(1″) is H or OH;and R^(1′) is a protecting group.
 19. The compound of claim 18 whereinR^(1′) is benzyl, 1-phenylethyl, 2-methoxybenzyl, 3-methoxybenzyl,4-methoxybenzyl, 2,4-dimethoxybenzyl, or diphenylmethyl; R^(1″) is OH;and n is 0, 1, 2 or
 3. 20. The compound of either claim 18 or 19 whereinR^(1′) is benzyl and n is 2.